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Background: Astrocytes, the most abundant glial cell type in the brain, will convert into the reactive state in response to proteotoxic stress such as tau accumulation, a characteristic feature of Alzheimer's disease (AD) and other tauopathies. The formation of reactive astrocytes is partially attributed to the disruption of autophagy lysosomal signaling, and inhibiting of some histone deacetylases (HDACs) has been demonstrated to reduce the molecular and functional characteristics of reactive astrocytes. However, the precise role of autophagy lysosomal signaling in astrocytes that regulates tau pathology remains unclear. Methods: We investigated the expression of class IIa HDAC7 in astrocytes from AD patients and PS19 mice. PS19 mice were treated with AAVs expressing shRNA for HDAC7 with astrocyte-specific promoter and with a selective class IIa HDAC inhibitor, TMP195, and the effects on tau pathology, gliosis, synaptic plasticity and cognition-related behavioral performance were measured. Tau uptake and degradation assays in cultured astrocytes were utilized to investigate the role of HDAC7 on astrocyte-mediated tau clearance. Immunoprecipitation, immunofluorescence, western blotting, RT-qPCR, mass spectrometric, and luciferase reporter assay were used to identify HDAC7 substrates, modification site and related signaling pathways in astrocyte-tau clearance. We generated a new antibody to clarify the role of HDAC7-mediated signaling in AD patients and PS19 mice. Results: Here, we found that the level of histone deacetylase 7 (HDAC7) was remarkably increased in the astrocytes of AD patients and P301S tau transgenic (PS19) mice. Genetic or pharmacological inhibition of HDAC7 effectively enhanced astrocytic clearance of tau with improved cognitive functions in PS19 mice. HDAC7 could modulate astrocytic uptake and lysosomal degradation of tau proteins through a transcriptional factor EB (TFEB) acetylation-dependent manner. Specifically, deacetylation of TFEB at K310 site by HDAC7 prevented TFEB nuclear translocation with reduced lysosomal biogenesis and tau clearance in astrocytes, whereas inhibiting HDAC7 restored astrocytic TFEB acetylation level at K310 with improved tau pathology and cognitive functions in PS19 mice. Conclusions: Our findings suggest that upregulation of HDAC7 induces AD-like tau pathologies via deacetylating TFEB and inhibiting lysosomal biogenesis in astrocytes, and downregulating HDAC7-TFEB signaling is promising for arresting AD and other tauopathies. [ABSTRACT FROM AUTHOR]

Ovarian cancer is of the most lethal malignancy and causes serious threat to women health worldwide. A deep understanding of molecular mechanisms underlying ovarian cancer progression is critical for the development of promising therapeutic strategies. In this study, we aimed to employ immunohistochemistry to determine the protein level of HDAC7 in patient tissues, our data showed HDAC7 levels are upregulated in tumour tissues. In addition, we also performed Kaplan–Meier survival analysis to investigate the association between HDAC7 expression and clinical prognosis, and found that HDAC7 expression was associated with poor prognosis in ovarian cancer patients. Inhibition of HDAC7 cells resulted in lower cell proliferation, invasion and colony formation. Furthermore, we also found that HDAC7 inhibition suppressed PI3K/AKT/mTOR pathway. In contrast, exogenous HDAC7 expression activated the PI3K/AKT/mTOR pathway in HDAC7 knockout cells and rescued the cell proliferation, invasion and colony formation. However, inhibition of p‐AKT induced lower cell proliferation, metastasis and colony formation abilities. In murine model, HDAC7 KO significantly decreased the tumour burden. These data indicate that HDAC7 is involved in regulation of PI3K/AKT/mTOR pathway and targeting of HDAC7 could be potential therapeutic strategy in the treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

Class IIa histone deacetylases (Class IIa HDACs) play critical roles in regulating essential cellular metabolism and inflammatory pathways. However, dissecting the specific roles of each class IIa HDAC isoform is hindered by the pan‐inhibitory effect of current inhibitors and a lack of tools to probe their functions beyond epigenetic regulation. In this study, a novel PROTAC‐based compound B4 is developed, which selectively targets and degrades HDAC7, resulting in the effective attenuation of a specific set of proinflammatory cytokines in both lipopolysaccharide (LPS)‐stimulated macrophages and a mouse model. By employing B4 as a molecular probe, evidence is found for a previously explored role of HDAC7 that surpasses its deacetylase function, suggesting broader implications in inflammatory processes. Mechanistic investigations reveal the critical involvement of HDAC7 in the Toll‐like receptor 4 (TLR4) signaling pathway by directly interacting with the TNF receptor‐associated factor 6 and TGFβ‐activated kinase 1 (TRAF6‐TAK1) complex, thereby initiating the activation of the downstream mitogen‐activated protein kinase/nuclear factor‐κB (MAPK/NF‐κB) signaling cascade and subsequent gene transcription. This study expands the insight into HDAC7's role within intricate inflammatory networks and highlights its therapeutic potential as a novel target for anti‐inflammatory treatments. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the leading cancers worldwide, with metastasis being a major cause of high mortality rates among patients. In this study, dysregulated gene Tweety homolog 3 (TTYH3) was identified by Gene Expression Omnibus database. Public databases were used to predict potential competing endogenous RNAs (ceRNAs) for TTYH3. Quantitative real‐time polymerase chain reaction, western blot, and immunohistochemistry were utilized to analyze TTYH3 and histone deacetylase 7 (HDAC7) levels. Luciferase assays confirmed miR‐1271‐5p directly targeting the 3′ untranslated regions of TTYH3 and HDAC7. In vitro experiments such as transwell and human umbilical vein endothelial cell tube formation, as well as in vivo mouse models, were conducted to assess the biological functions of TTYH3 and HDAC7. We discovered that upregulation of TTYH3 in CRC promotes cell migration by affecting the Epithelial–mesenchymal transition pathway, which was independent of its ion channel activity. Mechanistically, TTYH3 and HDAC7 functioned as ceRNAs, reciprocally regulating each other's expression. TTYH3 competes for binding miR‐1271‐5p, increasing HDAC7 expression, facilitating CRC metastasis and angiogenesis. This study reveals the critical role of TTYH3 in promoting CRC metastasis through ceRNA crosstalk, offering new insights into potential therapeutic targets for clinical intervention. [ABSTRACT FROM AUTHOR]

Histones have a vital function as components of nucleosomes, which serve as the fundamental building blocks of chromatin. Histone deacetylases (HDACs), which target histones, suppress gene transcription by compacting chromatin. This implies that HDACs have a strong connection to the suppression of gene transcription. Histone deacetylase 7 (HDAC7), a member of the histone deacetylase family, may participate in multiple cellular pathophysiological processes and activate relevant signaling pathways to facilitate the progression of different tumors by exerting deacetylation. In recent years, HDAC7 has been increasingly studied in the pathogenesis of tumors. Studies that are pertinent have indicated that it has a significant impact on the growth and metastasis of tumors, the formation of the vascular microenvironment, and the emergence of resistance to drugs. Therefore, HDAC7 could potentially function as a potent predictor for tumor prognosis and a promising target for mitigating drug resistance in tumors. This review primarily concentrates on elucidating the structure and function of HDAC7, its involvement in the development of various tumors, and its interplay with relevant signaling pathways. Meanwhile, we briefly discuss the research direction and prospect of HDAC7. [ABSTRACT FROM AUTHOR]

Abstract Colorectal cancer (CRC) is one of the leading cancers worldwide, with metastasis being a major cause of high mortality rates among patients. In this study, dysregulated gene Tweety homolog 3 (TTYH3) was identified by Gene Expression Omnibus database. Public databases were used to predict potential competing endogenous RNAs (ceRNAs) for TTYH3. Quantitative real‐time polymerase chain reaction, western blot, and immunohistochemistry were utilized to analyze TTYH3 and histone deacetylase 7 (HDAC7) levels. Luciferase assays confirmed miR‐1271‐5p directly targeting the 3′ untranslated regions of TTYH3 and HDAC7. In vitro experiments such as transwell and human umbilical vein endothelial cell tube formation, as well as in vivo mouse models, were conducted to assess the biological functions of TTYH3 and HDAC7. We discovered that upregulation of TTYH3 in CRC promotes cell migration by affecting the Epithelial–mesenchymal transition pathway, which was independent of its ion channel activity. Mechanistically, TTYH3 and HDAC7 functioned as ceRNAs, reciprocally regulating each other's expression. TTYH3 competes for binding miR‐1271‐5p, increasing HDAC7 expression, facilitating CRC metastasis and angiogenesis. This study reveals the critical role of TTYH3 in promoting CRC metastasis through ceRNA crosstalk, offering new insights into potential therapeutic targets for clinical intervention.

Abstract Background Mesenchymal stem cells (MSCs) are widely used in a variety of tissue regeneration and clinical trials due to their multiple differentiation potency. However, it remains challenging to maintain their replicative capability during in vitro passaging while preventing their premature cellular senescence. Forkhead Box P1 (FOXP1), a FOX family transcription factor, has been revealed to regulate MSC cell fate commitment and self-renewal capacity in our previous study. Methods Mass spectra analysis was performed to identify acetylation sites in FOXP1 protein. Single and double knockout mice of FOXP1 and HDAC7 were generated and analyzed with bone marrow MSCs properties. Gene engineering in human embryonic stem cell (hESC)-derived MSCs was obtained to evaluate the impact of FOXP1 key modification on MSC self-renewal potency. Results FOXP1 is deacetylated and potentiated by histone deacetylase 7 (HDAC7) in MSCs. FOXP1 and HDAC7 cooperatively sustain bone marrow MSC self-renewal potency while attenuating their cellular senescence. A mutation within human FOXP1 at acetylation site (T176G) homologous to murine FOXP1 T172G profoundly augmented MSC expansion capacity during early passages. Conclusion These findings reveal a heretofore unanticipated mechanism by which deacetylation of FOXP1 potentiates self-renewal of MSC and protects them from cellular senescence. Acetylation of FOXP1 residue T172 as a critical modification underlying MSC proliferative capacity. We suggest that in vivo gene editing of FOXP1 may provide a novel avenue for manipulating MSC capability during large-scale expansion in clinical trials.

The conserved multiple PDZ-domain containing protein PATJ stabilizes the Crumbs-Pals1 complex to regulate apical-basal polarity and tight junction formation in epithelial cells. However, the molecular mechanism of PATJ’s function in these processes is still unclear. In this study, we demonstrate that knockout of PATJ in epithelial cells results in tight junction defects as well as in a disturbed apical-basal polarity and impaired lumen formation in three-dimensional cyst assays. Mechanistically, we found PATJ to associate with and inhibit histone deacetylase 7 (HDAC7). Inhibition or downregulation of HDAC7 restores polarity and lumen formation. Gene expression analysis of PATJ-deficient cells revealed an impaired expression of genes involved in cell junction assembly and membrane organization, which is rescued by the downregulation of HDAC7. Notably, the function of PATJ regulating HDAC7-dependent cilia formation does not depend on its canonical interaction partner, Pals1, indicating a new role of PATJ, which is distinct from its function in the Crumbs complex. By contrast, polarity and lumen phenotypes observed in Pals1- and PATJ-deficient epithelial cells can be rescued by inhibition of HDAC7, suggesting that the main function of this polarity complex in this process is to modulate the transcriptional profile of epithelial cells by inhibiting HDAC7. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells (MSCs) are widely used in a variety of tissue regeneration and clinical trials due to their multiple differentiation potency. However, it remains challenging to maintain their replicative capability during in vitro passaging while preventing their premature cellular senescence. Forkhead Box P1 (FOXP1), a FOX family transcription factor, has been revealed to regulate MSC cell fate commitment and self-renewal capacity in our previous study. Methods: Mass spectra analysis was performed to identify acetylation sites in FOXP1 protein. Single and double knockout mice of FOXP1 and HDAC7 were generated and analyzed with bone marrow MSCs properties. Gene engineering in human embryonic stem cell (hESC)-derived MSCs was obtained to evaluate the impact of FOXP1 key modification on MSC self-renewal potency. Results: FOXP1 is deacetylated and potentiated by histone deacetylase 7 (HDAC7) in MSCs. FOXP1 and HDAC7 cooperatively sustain bone marrow MSC self-renewal potency while attenuating their cellular senescence. A mutation within human FOXP1 at acetylation site (T176G) homologous to murine FOXP1 T172G profoundly augmented MSC expansion capacity during early passages. Conclusion: These findings reveal a heretofore unanticipated mechanism by which deacetylation of FOXP1 potentiates self-renewal of MSC and protects them from cellular senescence. Acetylation of FOXP1 residue T172 as a critical modification underlying MSC proliferative capacity. We suggest that in vivo gene editing of FOXP1 may provide a novel avenue for manipulating MSC capability during large-scale expansion in clinical trials. [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDACs) catalyse removal of acetyl groups from lysine residues on both histone and non‐histone proteins to control numerous cellular processes. Of the 11 zinc‐dependent classical HDACs, HDAC4, 5, 7 and 9 are class IIa HDAC enzymes that regulate cellular and developmental processes through both enzymatic and non‐enzymatic mechanisms. Over the last two decades, HDAC7 has been associated with key roles in numerous physiological and pathological processes. Molecular, cellular, in vivo and disease association studies have revealed that HDAC7 acts through multiple mechanisms to control biological processes in immune cells, osteoclasts, muscle, the endothelium and epithelium. This HDAC protein regulates gene expression, cell proliferation, cell differentiation and cell survival and consequently controls development, angiogenesis, immune functions, inflammation and metabolism. This review focuses on the cell biology of HDAC7, including the regulation of its cellular localisation and molecular mechanisms of action, as well as its associative and causal links with cancer and inflammatory, metabolic and fibrotic diseases. We also review the development status of small molecule inhibitors targeting HDAC7 and their potential for intervention in different disease contexts. [ABSTRACT FROM AUTHOR]

Abstract Background Histone deacetylases (HDACs) play crucial roles in cancers, but the role and mechanism of HDAC7 in NSCLC have not been fully understood. Methods A total of 319 patients with non-small cell lung cancer (NSCLC) who underwent surgery were enrolled in this study. Immunohistochemistry and Kaplan–Meier survival analysis were performed to investigate the relationship between HDAC7, fibroblast growth factor 18 (FGF18) expression, and clinicopathologic characteristics. Cell functional experiments were implemented both in vivo and in vitro to investigate the effects on NSCLC cell proliferation and metastasis. Recombinant lentivirus–meditated in vivo gene overexpression or knockdown, real-time polymerase chain reaction (PCR), western blotting, and coimmunoprecipitation assays were applied to clarify the underlying molecular mechanism of HDAC7 in promoting NSCLC progression. Results The elevated expression of HDAC7 or FGF18 was positively correlated with poor prognosis, tumor–node–metastasis (TNM) stage, and tumor differentiation of NSCLC patients. NSCLC patients with co-expressed HDAC7 and FGF18 suffered the worst prognosis. HDAC7 overexpression promoted NSCLC proliferation and metastasis by upregulating FGF18. Conversely, overexpression of FGF18 reversed the attenuated ability in tumor growth and metastasis mediated by downregulating HDAC7. In terms of mechanism, our results suggested that the interaction of HDAC7 with β-catenin caused decreased β-catenin acetylation level at Lys49 and decreased phosphorylation level at Ser45. As a consequence, the HDAC7-mediated posttranslational modification of β-catenin facilitated nuclear transfer and activated FGF18 expression via binding to TCF4. Furthermore, deubiquitinase USP10 interacted with and stabilized HDAC7. The suppression of USP10 significantly accelerated the degradation of HDAC7 and weakened NSCLC growth and migration. Conclusions Our findings reveal that HDAC7 promotes NSCLC progression through being stabilized by USP10 and activating the β-catenin-FGF18 pathway. Targeting this novel pathway may be a promising strategy for further developments in NSCLC therapy.

Introduction: The objective of this study was to determine the NF-kappaB pathway, hub genes, and transcription factors (TFs) in monocytes implicated in the progression of neurovascular-related sepsis-induced cardiomyopathy (SIC) as well as potential miRNAs with regulatory functions. Methods: : Sepsis-induced cardiomyopathy—and heart failure (HF)-related differentially expressed genes (DEGs) between SIC and HF groups were identified separately by differential analysis. In addition, DEGs and differentially expressed miRNAs (DEmiRNAs) in monocytes between sepsis and the HC group were identified. Then, common DEGs in SIC, HF, and monocyte groups were identified by intersection analysis. Based on the functional pathways enriched by these DEGs, genes related to the NF-kB-inducing kinase (NIK)/NF-kappaB signaling pathway were selected for further intersection analysis to obtain hub genes. These common DEGs, together with sepsis-related DEmiRNAs, were used to construct a molecular interplay network and to identify core TFs in the network. Results: : A total of 153 upregulated genes and 25 downregulated genes were obtained from SIC-, HF-, and monocyte-related DEGs. Functional pathway analysis revealed that the upregulated genes were enriched in NF-κB signaling pathway. A total of eight genes associated with NF-κB signaling pathway were then further identified from the 178 DEGs. In combination with sepsis-related DEmiRNAs, HDAC7/ACTN4 was identified as a key transcriptional regulatory pair in the progression of SIC and in monocyte regulation. hsa-miR-23a-3p, hsa-miR-3175, and hsa-miR-23b-3p can regulate the progression of SIC through the regulation of HDAC7/ACTN4. Finally, gene set enrichment analysis (GSEA) suggested that HDAC7/ACTN4 may be associated with apoptosis in addition to the inflammatory response. Conclusion: : hsa-miR-23a-3p, hsa-miR-3175, and hsa-miR-23b-3p are involved in SIC progression by regulating NF-κB signaling signaling pathway-related HDAC7/ACTN4 in monocytes and cardiac tissue cells. These mechanisms may contribute to sepsis-induced neurovascular damage. [ABSTRACT FROM AUTHOR]

Abstract Background Histone deacetylase (HDAC) inhibition was reported to ameliorate lung fibrosis in animal models. However, little is known about the underlying mechanism of HDAC7 in the regulation of CTGF production in lung fibroblasts. Methods The role of HDAC7 in CTGF production caused by ET-1 stimulation in WI-38 cells (human lung fibroblast) was examined. We also evaluated the expression of HDAC7 in the lung of ovalbumin-induced airway fibrosis model. Statistical data were shown as mean ± standard error. Results ET-1-stimulated CTGF and α-SMA expression was attenuated by small interfering (si)RNA interference of HDAC7. ET-1 promoted HDAC7 translocation from the cytosol to nucleus. ET-1-stimulated CTGF expression was reduced by the transfection of p300 siRNA. ET-1 induced an increase in p300 activity. Furthermore, the acetylation of c-Jun was time-dependently induced by ET-1 stimulation, which was reduced by transfection of either HDAC7 or p300 siRNA. Both transfection of HDAC7 and p300 siRNA suppressed the ET-1-increased activity of AP-1-luciferase. Moreover, the presence of HDAC7 was required for ET-1-stimulated formation of HDAC7, p300, and AP-1 complex and recruitment to the CTGF promoter region. In an ovalbumin-induced airway fibrosis model, the protein level of HDAC7 was increased in the lung tissue, and the distribution of HDAC7 was colocalized with α-SMA-positive cells in the subepithelial layer of the airway. Conclusions ET-1 activates HDAC7 to initiate AP-1 transcriptional activity by recruiting p300 and eventually promotes the production of CTGF. HDAC7 might play a vital role in airway fibrosis and have the potential to be developed as a therapeutic target.

IntroductionThe objective of this study was to determine the NF-kappaB pathway, hub genes, and transcription factors (TFs) in monocytes implicated in the progression of neurovascular-related sepsis-induced cardiomyopathy (SIC) as well as potential miRNAs with regulatory functions.Methods: Sepsis-induced cardiomyopathy—and heart failure (HF)-related differentially expressed genes (DEGs) between SIC and HF groups were identified separately by differential analysis. In addition, DEGs and differentially expressed miRNAs (DEmiRNAs) in monocytes between sepsis and the HC group were identified. Then, common DEGs in SIC, HF, and monocyte groups were identified by intersection analysis. Based on the functional pathways enriched by these DEGs, genes related to the NF-kB-inducing kinase (NIK)/NF-kappaB signaling pathway were selected for further intersection analysis to obtain hub genes. These common DEGs, together with sepsis-related DEmiRNAs, were used to construct a molecular interplay network and to identify core TFs in the network.Results: A total of 153 upregulated genes and 25 downregulated genes were obtained from SIC-, HF-, and monocyte-related DEGs. Functional pathway analysis revealed that the upregulated genes were enriched in NF-κB signaling pathway. A total of eight genes associated with NF-κB signaling pathway were then further identified from the 178 DEGs. In combination with sepsis-related DEmiRNAs, HDAC7/ACTN4 was identified as a key transcriptional regulatory pair in the progression of SIC and in monocyte regulation. hsa-miR-23a-3p, hsa-miR-3175, and hsa-miR-23b-3p can regulate the progression of SIC through the regulation of HDAC7/ACTN4. Finally, gene set enrichment analysis (GSEA) suggested that HDAC7/ACTN4 may be associated with apoptosis in addition to the inflammatory response.Conclusion: hsa-miR-23a-3p, hsa-miR-3175, and hsa-miR-23b-3p are involved in SIC progression by regulating NF-κB signaling signaling pathway-related HDAC7/ACTN4 in monocytes and cardiac tissue cells. These mechanisms may contribute to sepsis-induced neurovascular damage.

Background: Histone deacetylases (HDACs) play crucial roles in cancers, but the role and mechanism of HDAC7 in NSCLC have not been fully understood. Methods: A total of 319 patients with non-small cell lung cancer (NSCLC) who underwent surgery were enrolled in this study. Immunohistochemistry and Kaplan–Meier survival analysis were performed to investigate the relationship between HDAC7, fibroblast growth factor 18 (FGF18) expression, and clinicopathologic characteristics. Cell functional experiments were implemented both in vivo and in vitro to investigate the effects on NSCLC cell proliferation and metastasis. Recombinant lentivirus–meditated in vivo gene overexpression or knockdown, real-time polymerase chain reaction (PCR), western blotting, and coimmunoprecipitation assays were applied to clarify the underlying molecular mechanism of HDAC7 in promoting NSCLC progression. Results: The elevated expression of HDAC7 or FGF18 was positively correlated with poor prognosis, tumor–node–metastasis (TNM) stage, and tumor differentiation of NSCLC patients. NSCLC patients with co-expressed HDAC7 and FGF18 suffered the worst prognosis. HDAC7 overexpression promoted NSCLC proliferation and metastasis by upregulating FGF18. Conversely, overexpression of FGF18 reversed the attenuated ability in tumor growth and metastasis mediated by downregulating HDAC7. In terms of mechanism, our results suggested that the interaction of HDAC7 with β-catenin caused decreased β-catenin acetylation level at Lys49 and decreased phosphorylation level at Ser45. As a consequence, the HDAC7-mediated posttranslational modification of β-catenin facilitated nuclear transfer and activated FGF18 expression via binding to TCF4. Furthermore, deubiquitinase USP10 interacted with and stabilized HDAC7. The suppression of USP10 significantly accelerated the degradation of HDAC7 and weakened NSCLC growth and migration. Conclusions: Our findings reveal that HDAC7 promotes NSCLC progression through being stabilized by USP10 and activating the β-catenin-FGF18 pathway. Targeting this novel pathway may be a promising strategy for further developments in NSCLC therapy. [ABSTRACT FROM AUTHOR]

Abstract Background Mounting evidences have displayed that the dysregulation of miRNAs plays important roles in the pathogenesis of gastric cancer (GC). The purpose of this study was to explore the biological functions and potential mechanism of miR-489 in GC progression. Methods Quantitative real-time PCR (qRT-PCR) and western blot were performed to examine the mRNA expression and protein levels of miR-489 and HDAC7. The relationship between miR-489 and HDAC7 was analyzed by Spearman rank correlation. 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay and transwell assays were conducted for determining the effect of miR-489 and HDAC7 on GC cell viability, migration, and invasion. TargetScan and luciferase reporter assay were used to confirm the target gene of miR-489 in GC cells. Results The findings showed that miR-489 was dramatically decreased in GC tissues and GC cell lines (SGC-7901 and MKN45). Moreover, it was closely correlated with overall survival (OS) and progression-free survival (PFS) of GC patients. Downregulation of miR-489 significantly promoted GC cell proliferation, invasion, and migration. Additionally, HDAC7 was confirmed as the direct target of miR-489. Knockdown of HDAC7 exerted inhibited effect on GC progression and it markedly overturned miR-489 inhibitor-medicated effect on GC cells. More interestingly, via targeting HDAC7, miR-489 blocked the activation of PI3K/AKT pathway in GC cells. Conclusions Correctively, miR-489 played as a tumor suppressor in GC cell growth by targeting HDAC7, and miR-489 might function as a novel biomarker for diagnosis or therapeutic targets of human GC.

Background: Glioblastoma multiforme (GBM) is an aggressive brain tumour for which current traditional treatment approaches have been unsuccessful, owing to the high genetic heterogeneity and immunosuppressive tumour microenvironment. Methods: Single-cell and spatial transcriptomic data revealed the niche-specific enrichment of mesenchymal-like (MES-like) GBM cells and monocyte-derived macrophages (MDMs); Gain- and loss-of-function assays of HDAC7 was confirmed both in vitro and in vivo assays. Mechanistically, mass spectrum, RNA immunoprecipitation (RIP), and co-immunoprecipitation assays were conducted. Results: We found that HDAC7, which upregulated by TRIM28-mediated sumoylation at the protein levels, inhibited SOX8 expression by mediating H3K27 deacetylation. And the down-regulated SOX8 facilitated the transcriptional activity of JUN, to induce LGALS3 secretion, which then bind to the membrane protein ITGB1 on GSC and MDMs in the autocrine and paracrine manners to facilitate the transformation of the mesenchymal phenotype of GBM and the M2 polarization of MDMs, respectively. In turn, LGALS3 could also secreted by M2 MDMs to promote MES transition of GBM in a paracrine manner, creating a positive feedback loop. In translational medicine, we found that blocking LGALS3 improved the therapeutic sensitivity of HDAC inhibitors. Conclusions: Our findings revealed the role of the novel HDAC7-H3K27ac-SOX8/JUN-LGALS3-ITGB1 axis in maintaining the crosstalk between MES GBM and M2 MDM, highlighting that HDAC7 and LGALS3 may serve as potential prognostic biomarkers and therapeutic targets in GBM., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Postnatal mammalian cardiomyocytes (CMs) rapidly lose proliferative capacity and exit the cell cycle and undergo further differentiation and maturation. Cell cycle activation has been a major strategy to stimulate postnatal CM proliferation, albeit achieving modest effects. One impediment is that postnatal CMs may need to undergo dedifferentiation before proliferation, if not simultaneously. Here, we report that overexpression of Hdac7 in neonatal mouse CMs results in significant CM dedifferentiation and proliferation. Mechanistically, we show that HDAC7-mediated CM proliferation is contingent on dedifferentiation, which is accomplished through suppressing MEF2. Hdac7 overexpression in CM shifts the chromatin state from binding MEF2, which favors the differentiation transcriptional program to AP-1, which favors the proliferative transcriptional program. Further, we found that HDAC7 interacts with minichromosome maintenance complex (MCM) components to initiate cell cycle progression. Our findings reveal that HDAC7 promotes CM proliferation by its dual action on CM dedifferentiation and proliferation, uncovering a potential new strategy for heart regeneration/repair., (© The Author(s) 2024. Published by Oxford University Press on behalf of Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.)

Background: Decitabine is a potent anticancer hypomethylating agent and changes the gene expression through the gene's promoter demethylation and also independently from DNA demethylation. So, the present study was designed to distinguish whether Decitabine, in addition to inhibitory effects on DNA methyltransferase, can change HDAC3 and HDAC7 mRNA expression in NALM-6 and HL-60 cancer cell lines. Methods: HL-60, NALM-6, and normal cells were cultured, and the Decitabine treatment dose was obtained (1 μM) through the MTT assay. Finally, HDAC3 and HDAC7 mRNA expression were measured by Real-Time PCR in HL-60 and NALM-6 cancerous cells before and after treatment. Furthermore, HDAC3 and HDAC7 mRNA expression in untreated HL-60 and NALM-6 cancerous cells were compared to normal cells. Results: Our results revealed that the expression of HDAC3 and HDAC7 in HL-60 and NALM-6 cells increases as compared to normal cells. After treatment of HL-60 and NALM-6 cells with Decitabine, HDAC3, and HDAC7 mRNA expression were decreased significantly. Conclusions: Our data confirmed that the effects of Decitabine are not limited to direct hypomethylation of DNMTs, but it can indirectly affect other epigenetic factors, such as HDACs activity, through converging pathways. [ABSTRACT FROM AUTHOR]

HDAC7 is a pleiotropic transcriptional coregulator that controls different cellular fates. Here, we demonstrate that in human mammary epithelial cells, HDAC7 sustains cell proliferation and favours a population of stem‐like cells, by maintaining a proficient microenvironment. In particular, HDAC7 represses a repertoire of cytokines and other environmental factors, including elements of the insulin‐like growth factor signalling pathway, IGFBP6 and IGFBP7. This HDAC7‐regulated secretome signature predicts negative prognosis for luminal A breast cancers. ChIP‐seq experiments revealed that HDAC7 binds locally to the genome, more frequently distal from the transcription start site. HDAC7 can colocalize with H3K27‐acetylated domains and its deletion further increases H3K27ac at transcriptionally active regions. HDAC7 levels are increased in RAS‐transformed cells, in which this protein was required not only for proliferation and cancer stem‐like cell growth, but also for invasive features. We show that an important direct target of HDAC7 is IL24, which is sufficient to suppress the growth of cancer stem‐like cells.

Background: Histone deacetylase (HDAC) inhibition was reported to ameliorate lung fibrosis in animal models. However, little is known about the underlying mechanism of HDAC7 in the regulation of CTGF production in lung fibroblasts. Methods: The role of HDAC7 in CTGF production caused by ET-1 stimulation in WI-38 cells (human lung fibroblast) was examined. We also evaluated the expression of HDAC7 in the lung of ovalbumin-induced airway fibrosis model. Statistical data were shown as mean ± standard error. Results: ET-1-stimulated CTGF and α-SMA expression was attenuated by small interfering (si)RNA interference of HDAC7. ET-1 promoted HDAC7 translocation from the cytosol to nucleus. ET-1-stimulated CTGF expression was reduced by the transfection of p300 siRNA. ET-1 induced an increase in p300 activity. Furthermore, the acetylation of c-Jun was time-dependently induced by ET-1 stimulation, which was reduced by transfection of either HDAC7 or p300 siRNA. Both transfection of HDAC7 and p300 siRNA suppressed the ET-1-increased activity of AP-1-luciferase. Moreover, the presence of HDAC7 was required for ET-1-stimulated formation of HDAC7, p300, and AP-1 complex and recruitment to the CTGF promoter region. In an ovalbumin-induced airway fibrosis model, the protein level of HDAC7 was increased in the lung tissue, and the distribution of HDAC7 was colocalized with α-SMA-positive cells in the subepithelial layer of the airway. Conclusions: ET-1 activates HDAC7 to initiate AP-1 transcriptional activity by recruiting p300 and eventually promotes the production of CTGF. HDAC7 might play a vital role in airway fibrosis and have the potential to be developed as a therapeutic target. [ABSTRACT FROM AUTHOR]

Persistent symptoms of depression indicate the adaptive involvement of stable molecules in the brain that may be manifested at the level of chromatin remodeling, such as histone acetylation. Former studies have identified alterations in histone acetylation and deacetylation in several animal models about depression. However, the specific histone deacetylases related with depression are needed to be explored. Here, social avoidance behaviors, anxiety-, and depression-like behaviors were all found in mice suffered from chronic social defeat stress. Moreover, we also discovered that the amount of the class II histone deacetylase, HDAC7 rather than HDAC2, was significantly decreased in the nucleus accumbens of defeated mice, which suggested that HDAC7 might be a crucial histone deacetylase in a chronic social defeat stress model. Our data showed that the depressive-like behaviors induced by chronic social defeat stress were associated with HDAC7 reduction in nucleus accumbens. HDAC7 might be a promising therapeutic target for depression.

Abstract Background Zinc-finger protein-326 (ZNF326) was initially found in the NIH3T3 cell line to regulate cell growth, however, the expression and underlying role of ZNF326 in human tumours, especially in glioma, is not fully understood. Methods Immunohistochemistry was applied to detect the expression of ZNF326 in glioma tissues, and statistical analysis was used to analyse the relationship between ZNF326 expression and clinicopathological factors. The effect of ZNF326 on glioma cells proliferation and invasion was conducted by functional experiments both in vivo and in vitro. Chromatin immunoprecipitation and dual-luciferase assays were performed to demonstrate that histone deacetylase enzyme-7 (HDAC7) is the target gene of ZNF326. Immunoblotting, real-time PCR, GST-pulldown and co-immunoprecipitation assays were used to clarify the underlying role of ZNF326 on Wnt pathway activation. Results High nuclear expression of ZNF326 was observed in glioma cell lines and tissues, and closely related with advanced tumour grade in the patients. Moreover, ectopic ZNF326 expression promoted the proliferation and invasiveness of glioma cells. Mechanistically, ZNF326 could activate HDAC7 transcription by binding to a specific promoter region via its transcriptional activation domain and zinc-finger structures. The interaction of the up-regulated HDAC7 with β-catenin led to a decrease in β-catenin acetylation level at Lys-49, followed by a decrease in β-catenin phosphorylation level at Ser-45. These changes in β-catenin posttranscriptional modification levels promoted its redistribution and import into the nucleus. Additionally, ZNF326 directly associated with β-catenin in the nucleus, and enhanced the binding of β-catenin to TCF-4, serving as a co-activator in stimulating Wnt pathway. Conclusions Our findings elucidated ZNF326 promotes the malignant phenotype of human glioma via ZNF326-HDAC7-β-catenin signalling. This study reveals the vital role and mechanism of ZNF326 in the malignant progression of glioma, and provides the reference for finding biomarkers and therapeutic targets for glioma.

Persistent symptoms of depression indicate the adaptive involvement of stable molecules in the brain that may be manifested at the level of chromatin remodeling, such as histone acetylation. Former studies have identified alterations in histone acetylation and deacetylation in several animal models about depression. However, the specific histone deacetylases related with depression are needed to be explored. Here, social avoidance behaviors, anxiety-, and depression-like behaviors were all found in mice suffered from chronic social defeat stress. Moreover, we also discovered that the amount of the class II histone deacetylase, HDAC7 rather than HDAC2, was significantly decreased in the nucleus accumbens of defeated mice, which suggested that HDAC7 might be a crucial histone deacetylase in a chronic social defeat stress model. Our data showed that the depressive-like behaviors induced by chronic social defeat stress were associated with HDAC7 reduction in nucleus accumbens. HDAC7 might be a promising therapeutic target for depression. [ABSTRACT FROM AUTHOR]

Previous reports that we have coauthored have shown that transcription factor ZNF326 can upregulate the expression of ERCC1 and HDAC7, and downregulate the expression of LTBP4 and ZNF383 in lung-cancer cells. However, whether tissue-specificity of the ZNF326 function exists in glioma tissue remains unclear. In this study, overexpression or knockdown of ZNF326 in glioma cells caused upregulation or downregulation, respectively, of the protein and micro RNA (mRNA) levels of ERCC1 and HDAC7. The levels of LTBP4 and ZNF383 were not significantly changed. Immunohistochemical results showed that ZNF326 was not only highly expressed in glioma but was also positively correlated with the expression of ERCC1 and HDAC7. Moreover, the expression of ERCC1 and HDAC7 was enhanced with the increase in tumor grade. However, there was no correlation between ZNF326 and the expression of LTBP4 and ZNF383. Therefore, the detection of ZNF326 , ERCC1, and HDAC7 expressions was useful for identifying different grades of glioma. [ABSTRACT FROM AUTHOR]

Background: Mounting evidences have displayed that the dysregulation of miRNAs plays important roles in the pathogenesis of gastric cancer (GC). The purpose of this study was to explore the biological functions and potential mechanism of miR-489 in GC progression. Methods: Quantitative real-time PCR (qRT-PCR) and western blot were performed to examine the mRNA expression and protein levels of miR-489 and HDAC7. The relationship between miR-489 and HDAC7 was analyzed by Spearman rank correlation. 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay and transwell assays were conducted for determining the effect of miR-489 and HDAC7 on GC cell viability, migration, and invasion. TargetScan and luciferase reporter assay were used to confirm the target gene of miR-489 in GC cells. Results: The findings showed that miR-489 was dramatically decreased in GC tissues and GC cell lines (SGC-7901 and MKN45). Moreover, it was closely correlated with overall survival (OS) and progression-free survival (PFS) of GC patients. Downregulation of miR-489 significantly promoted GC cell proliferation, invasion, and migration. Additionally, HDAC7 was confirmed as the direct target of miR-489. Knockdown of HDAC7 exerted inhibited effect on GC progression and it markedly overturned miR-489 inhibitor-medicated effect on GC cells. More interestingly, via targeting HDAC7, miR-489 blocked the activation of PI3K/AKT pathway in GC cells. Conclusions: Correctively, miR-489 played as a tumor suppressor in GC cell growth by targeting HDAC7, and miR-489 might function as a novel biomarker for diagnosis or therapeutic targets of human GC. [ABSTRACT FROM AUTHOR]

Abstract Background Lung cancer is the leading cause of cancer death worldwide. However, the molecular mechanisms underlying lung cancer development have not been fully understood. The functions of histone deacetylases (HDACs), a class of total eighteen proteins (HDAC1–11 and SIRT1–7 in mammals) that deacetylate histones and non-histone proteins, in cancers are largely unknown. Methods Hdac7 +/−/K-Ras mice and HDAC7-depleted human lung cancer cell lines were used as models for studying the function of Hdac7 gene in lung cancer. Kaplan-Meier survival analysis was performed to explore the relationship between HDAC7 expression and prognosis of human lung cancers. Recombinant lentivirus-mediated in vivo gene expression or knockdown, Western blotting, and pull-down assay were applied to investigate the underlying molecular mechanism by which Hdac7 promotes lung tumorigenesis. Results The number and burden of lung tumor were dramatically reduced in Hdac7 +/−/K-Ras mice compared to control K-Ras mice. Also, in Hdac7 +/−/K-Ras mice, cell proliferation was significantly inhibited and apoptosis in lung tumors was greatly enhanced. Similarly, cell proliferation and anchorage-independent growth of human lung cancer cell lines expressing shHDAC7 were also significantly suppressed and apoptosis was dramatically elevated respectively. Mechanistic study revealed that Hdac7 mutation in mouse lung tumors or HDAC7 depletion in human tumor cell lines resulted in significantly enhanced acetylation and tyrosine-phosphorylation of Stat3 and HDAC7 protein directly interacted with and deacetylateed STAT3. The Hdac7 mutant-mediated inhibitory effects on lung tumorigenesis in mice and cell proliferation/soft agar colony formation of human lung cancer cell lines were respectively reversed by expressing dnStat3. Finally, the high HDAC7 mRNA level was found to be correlated with poor prognosis of human lung cancer patients. Conclusion Our study suggests that Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation via deacetylating Stat3 and may shed a light on the design of new therapeutic strategies for human lung cancer.

HDAC7 is a pleiotropic transcriptional coregulator that controls different cellular fates. Here, we demonstrate that in human mammary epithelial cells, HDAC7 sustains cell proliferation and favours a population of stem‐like cells, by maintaining a proficient microenvironment. In particular, HDAC7 represses a repertoire of cytokines and other environmental factors, including elements of the insulin‐like growth factor signalling pathway, IGFBP6 and IGFBP7. This HDAC7‐regulated secretome signature predicts negative prognosis for luminal A breast cancers. ChIP‐seq experiments revealed that HDAC7 binds locally to the genome, more frequently distal from the transcription start site. HDAC7 can colocalize with H3K27‐acetylated domains and its deletion further increases H3K27ac at transcriptionally active regions. HDAC7 levels are increased in RAS‐transformed cells, in which this protein was required not only for proliferation and cancer stem‐like cell growth, but also for invasive features. We show that an important direct target of HDAC7 is IL24, which is sufficient to suppress the growth of cancer stem‐like cells. [ABSTRACT FROM AUTHOR]

Mushrooms can be considered a valuable source of natural bioactive compounds with potential polypharmacological effects due to their proven antimicrobial, antiviral, antitumor, and antioxidant activities. In order to identify new potential anticancer compounds, an in-house chemical database of molecules extracted from both edible and non-edible fungal species was employed in a virtual screening against the isoform 7 of the Histone deacetylase (HDAC). This target is known to be implicated in different cancer processes, and in particular in both breast and ovarian tumors. In this work, we proposed the ibotenic acid as lead compound for the development of novel HDAC7 inhibitors, due to its antiproliferative activity in human breast cancer cells (MCF-7). These promising results represent the starting point for the discovery and the optimization of new HDAC7 inhibitors and highlight the interesting opportunity to apply the “drug repositioning” paradigm also to natural compounds deriving from mushrooms.

We report that Histone Deacetylase 7 (HDAC7) controls the thymic effector programming of Natural Killer T (NKT) cells, and that interference with this function contributes to tissue-specific autoimmunity. Gain of HDAC7 function in thymocytes blocks both negative selection and NKT development, and diverts Vα14/Jα18 TCR transgenic thymocytes into a Tconv-like lineage. Conversely, HDAC7 deletion promotes thymocyte apoptosis and causes expansion of innate-effector cells. Investigating the mechanisms involved, we found that HDAC7 binds PLZF and modulates PLZF-dependent transcription. Moreover, HDAC7 and many of its transcriptional targets are human risk loci for IBD and PSC, autoimmune diseases that strikingly resemble the disease we observe in HDAC7 gain-of-function in mice. Importantly, reconstitution of iNKT cells in these mice mitigated their disease, suggesting that the combined defects in negative selection and iNKT cells due to altered HDAC7 function can cause tissue-restricted autoimmunity, a finding that may explain the association between HDAC7 and hepatobiliary autoimmunity.

Macroautophagy/autophagy is an important process responsible for protein turnover and cell survival in amino acid-deprived conditions, especially for leucine (Leu). With the dramatic advances in mass spectrometry, many new post-translational modifications (PTMs) have been identified. However, whether these PTMs regulate autophagy remains unclear. Here we found global lysine crotonylation levels are significantly upregulated during Leu deprivation-induced autophagy. A comprehensive crotonylome profiling showed that YWHA/14-3-3 proteins are significantly enriched in the Leu regulated-crotonylome. The inhibition of YWHAE/14-3-3ε crotonylation by mutating two crotonylated sites to arginine, K73R K78R, significantly attenuates autophagy induced by Leu deprivation. Molecular dynamics suggest that YWHAE K73 and K78 crotonylations decrease protein conformation and thermodynamic stability. Moreover, we found crotonylation of YWHAE releases PPM1B to dephosphorylate ULK1 and consequently activate autophagy. Decrotonylation of YWHAE is mediated by HDAC7 whose activity is inhibited significantly by Leu deprivation. Taken together, our finding reveals a critical role of YWHAE crotonylation in Leu deprivation-induced autophagy.

Aims/hypothesis: Pancreatic beta cell dysfunction is a prerequisite for the development of type 2 diabetes. Histone deacetylases (HDACs) may affect pancreatic endocrine function and glucose homeostasis through alterations in gene regulation. Our aim was to investigate the role of HDAC7 in human and rat pancreatic islets and clonal INS-1 beta cells (INS-1 832/13). Methods: To explore the role of HDAC7 in pancreatic islets and clonal beta cells, we used RNA sequencing, mitochondrial functional analyses, microarray techniques, and HDAC inhibitors MC1568 and trichostatin A. Results: Using RNA sequencing, we found increased HDAC7 expression in human pancreatic islets from type 2 diabetic compared with non-diabetic donors. HDAC7 expression correlated negatively with insulin secretion in human islets. To mimic the situation in type 2 diabetic islets, we overexpressed Hdac7 in rat islets and clonal beta cells. In both, Hdac7 overexpression resulted in impaired glucose-stimulated insulin secretion. Furthermore, it reduced insulin content, mitochondrial respiration and cellular ATP levels in clonal beta cells. Overexpression of Hdac7 also led to changes in the genome-wide gene expression pattern, including increased expression of Tcf7l2 and decreased expression of gene sets regulating DNA replication and repair as well as nucleotide metabolism. In accordance, Hdac7 overexpression reduced the number of beta cells owing to enhanced apoptosis. Finally, we found that inhibiting HDAC7 activity with pharmacological inhibitors or small interfering RNA-mediated knockdown restored glucose-stimulated insulin secretion in beta cells that were overexpressing Hdac7. Conclusions/interpretation: Taken together, these results indicate that increased HDAC7 levels caused beta cell dysfunction and may thereby contribute to defects seen in type 2 diabetic islets. Our study supports HDAC7 inhibitors as a therapeutic option for the treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Chromatin regulation and alternative splicing are both critical mechanisms guiding gene expression. Studies have demonstrated that histone modifications can influence alternative splicing decisions, but less is known about how alternative splicing may impact chromatin. Here, we demonstrate that several genes encoding histone-modifying enzymes are alternatively spliced downstream of T cell signaling pathways, including HDAC7, a gene previously implicated in controlling gene expression and differentiation in T cells. Using CRISPR-Cas9 gene editing and cDNA expression, we show that differential inclusion of HDAC7 exon 9 controls the interaction of HDAC7 with protein chaperones, resulting in changes to histone modifications and gene expression. Notably, the long isoform, which is induced by the RNA-binding protein CELF2, promotes expression of several critical T cell surface proteins including CD3, CD28, and CD69. Thus, we demonstrate that alternative splicing of HDAC7 has a global impact on histone modification and gene expression that contributes to T cell development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The myocyte enhancer factor 2 and histone deacetylase (MEF2-HDAC) axis is a master regulator of different developmental programs and adaptive responses in adults. In this paper, we have investigated the contribution of the axis to the regulation of epithelial morphogenesis, using 3D organotypic cultures of MCF10A cells as a model. We have demonstrated that MEF2 transcriptional activity is upregulated during acini formation, which coincides with exit from the proliferative phase. Upregulation of the transcription of MEF2 proteins is coupled to downregulation of HDAC7, which occurs independently from changes in mRNA levels, and proteasome- or autophagy-mediated degradation. During acini formation, the MEF2-HDAC axis contributes to the promotion of cell cycle exit, through the engagement of the CDK inhibitor CDKN1A. Only in proliferating cells can HDAC7 bind to the first intron of the CDKN1A gene, a region characterized by epigenetic markers of active promoters and enhancers. In cells transformed by the oncogene HER2 (ERBB2), acini morphogenesis is altered, MEF2 transcription is repressed and HDAC7 is continuously expressed. Importantly, reactivation of MEF2 transcriptional activity in these cells, through the use of a HER2 inhibitor or by enhancing MEF2 function, corrected the proliferative defect and re-established normal acini morphogenesis. [ABSTRACT FROM AUTHOR]

Background: Wilms' tumor (WT) is one of the most common malignant neoplasms of the urinary tract in children. Anaplastic histology (unfavorable histology) accounts for about 10% of whole WTs, and it is the single most important histologic predictor of treatment response and survival in patients with WT; however, until now the molecular basis of this phenotype is not very clearly. Methods: A real-time polymerase chain reaction (PCR) array was designed and tested. Next, the gene expression profile of pediatric anaplastic histology WT and normal adjacent tissues were analyzed. These expression data were anlyzed with Multi Experiment View (MEV) cluster software further. Datasets representing genes with altered expression profiles derived from cluster analyses were imported into the Ingenuity Pathway Analysis Tool (IPA). Results: 88 real-time PCR primer pairs for quantitative gene expression analysis of key genes involved in pediatric anaplastic histology WT were designed and tested. The gene expression profile of pediatric anaplastic histology WT is significantly different from adjacent normal controls; we identified 15 genes that are up-regulated and 16 genes that are down-regulated in the former. To investigate biological interactions of these differently regulated genes, datasets representing genes with altered expression profiles were imported into the IPA for further analysis, which revealed three significant networks: Cancer, Hematological Disease, and Gene Expression, which included 27 focus molecules and a significance score of 43. The IPA analysis also grouped the differentially expressed genes into biological mechanisms related to Cell Death and Survival 1.15E-12, Cellular Development 2.84E-11, Cellular Growth and Proliferation 2.84E-11, Gene Expression 4.43E-10, and DNA Replication, Recombination, and Repair 1.39E-07. The important upstream regulators of pediatric anaplastic histology WT were TP53 and TGFβ1 signaling (P = 1.15E-14 and 3.79E-13, respectively). Conclusions: Our study demonstrates that the gene expression profile of pediatric anaplastic histology WT is significantly different from adjacent normal tissues with real-time PCR array. We identified some genes that are dysregulated in pediatric anaplastic histology WT for the first time, such as HDAC7, and IPA analysis showed the most important pathways for pediatric anaplastic histology WT are TP53 and TGFβ1 signaling. This work may provide new clues into the molecular mechanisms behind pediatric anaplastic histology WT. [ABSTRACT FROM AUTHOR]

HDAC4, 5, 7 and 9 constitute the class IIa histone deacetylases (HDACs) within the large family of protein deacetylases. Class IIa HDACs have unique features that distinguish them from other HDACs. They contain an N-terminal domain that is required for their interaction with tissue-specific transcription factors and recruitment to their target genes. The N-terminal domain on class IIa HDACs also bears conserved serine residues that undergo signal-dependent phosphorylation, which brings about nuclear export of the enzymes and de-repression of their targets. One of the most important aspects of class IIa HDACs is their expression in specific tissues and organs within the organism, where they have crucial roles in development and differentiation processes. This review brings up to date our knowledge of the physiological and pathological functions of class IIa HDACs, focusing in particular on the most recent discoveries from in vivo studies of mouse model systems. [ABSTRACT FROM AUTHOR]